Solid pharmaceutical composition comprising amlodipine and losartan

ABSTRACT

The present invention provides a pharmaceutical composition for the prevention or treatment of cardiovascular disorders containing losartan or a pharmaceutically acceptable salt thereof; amlodipine or a pharmaceutically acceptable salt thereof; a disintegrant; and a coating agent. 
     The composition of the present invention, which has the best combination and optimum ratio of a disintegrant to a coating agent, shows sufficient strength and high dissolution rates under various pH environments, and thus, it is useful for the preparation of an excellent solid formulation exhibiting improved drug delivery efficiency and storage stability.

FIELD OF THE INVENTION

The present invention relates to a solid pharmaceutical compositioncomprising amlodipine and losartan as active ingredients which hasimproved dissolution rates and storage stability of them.

BACKGROUND OF THE INVENTION

In the treatment of hypertension, it is essential to maintain bloodpressure within a normal range rather than just control the symptomsthereof, thereby preventing life-threatening diseases such as stroke,heart failure, and coronary heart diseases (e.g., myocardialinfarction), and cardiovascular complications such as renal failure.Since long-term administration of an antihypertensive drug is requiredfor controlling blood pressure, selection of the drug should be madecarefully. Further, advanced therapy using a combination of two or moredrugs having pharmacological actions different from each other makes itpossible to improve preventive or therapeutic effects, while reducingside effects arising from the long-term administration of a drug bylowering the amounts of individual drugs.

Antihypertensive drugs commonly used may be divided into three majorcategories such as diuretics, sympatholytics and vasodilators based ontheir action mechanisms. Vasodilators, widely prescribedantihypertensive drugs, may be further divided into several groups suchas angiotensin converting enzyme (ACE) inhibitors, angiotensin IIreceptor blockers and calcium channel blockers based on theirpharmacological actions.

Amlodipine is the generic name for3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate, and amlodipine besylate is currently marketed asNorvasc®. Amlodipine blocks calcium channels, and is used for thetreatment of cardiovascular disorders such as angina, hypertension andcongestive heart failure.

Losartan is the generic name for2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol,which has been disclosed in U.S. Pat. Nos. 5,608,075; 5,138,069; and5,153,197, etc. Losartan potassium is currently available as Cozaar®.Losartan blocks the binding of angiotensin II, a vasoconstrictor, to itsreceptor. It is used for treating hypertension, heart failure, ischemicperipheral circulation disorder, myocardial ischemia (angina pectoris),diabetic neuropathy and glaucoma, and also used for preventing theprogression of heart failure post-myocardial infarction.

The present inventors found that a combined formulation of amlodipineand losartan having two distinct pharmacological action mechanisms isuseful for the treatment of hypertension, and have conducted intensivestudies on such a combined formulation. However, when the combinedformulation of amlodipine and losartan was prepared, undesirablegelation of losartan was observed. More particularly, losartan is easilydissolved in purified water or at a relatively high pH (e.g., pH 6.8,etc.) showing good dissolution patterns, but it is very slowly dissolvedat a low pH (e.g., pH 1.2 or 2.0) because of its gelation. As such, inthe combined formulation of amlodipine and losartan, amlodipine may alsobe trapped in the losartan gel due to the gelation of losartan,resulting in a decrease in dissolution rate.

An oral formulation generally undergoes disintegration and dissolutionin stomach, which has low pH contents. Accordingly, a low dissolutionrate of an active ingredient at a low pH (e.g., pH 1 or 2) cansignificantly affect its bioavailability.

In addition, considering that the gastric pH of a normal adult varieswidely in a range of 1.0 to 3.5 and Cmax of losartan after foodingestion is reduced by about 10% (PDR), development of a formulationcapable of maintaining a relatively constant dissolution rate despitesuch variations of gastric pH is needed to achieve maximum effect of adrug by maximizing drug absorption and minimizing variations in drugabsorption within an individual or among individuals. In this context,in case of a combined formulation of amlodipine and losartan, a highamount of at least one type of disintegrant is required to develop aformulation which shows little differences in dissolution rate at anormal range of gastric pH variations, and shows high dissolution rateby preventing the gelation of losartan under low pH conditions. However,a formulation using a relatively high content of disintegrant may haveproblems in its storage stability due to the water absorbing property ofthe disintegrant. More particularly, upon exposure to moisture, apharmaceutical composition using a high amount of disintegrant is likelyto show changes in its property and a decrease in its efficacy. Thus,there has been a need for developing a pharmaceutical composition withimproved storage stability, to prevent the decrease in dissolution rate.

The present inventors have therefore endeavored to develop a combinedformulation comprising losartan and amlodipine, for the prevention ortreatment of cardiovascular disorders, in the form of a solidformulation which has improved dissolution rate, stability andtherapeutic efficacy. As a result, the present inventors have foundthat, by employing a disintegrant and a coating agent in a compositionat a specific ratio, low dissolution rate arising from the losartangelation in an acidic environment can be significantly improved, whilechanges in the properties of the composition upon exposure to moisturecan be prevented, affording efficient delivery of its active ingredientsand improved storage stability.

In the present patent application, reference will be made to articlesand patent documents along with citations thereto. The contents of thearticles and patent documents are herein incorporated by reference intheir entireties, and thereby the level of technical field to which thepresent invention belong and the disclosure of the present invention areexplained with more clarity.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide apharmaceutical composition for the prevention or treatment ofcardiovascular disorders.

In accordance with one object of the present invention, there isprovided a pharmaceutical composition for the prevention or treatment ofcardiovascular disorders comprising (A) losartan or a pharmaceuticallyacceptable salt thereof; (B) amlodipine or a pharmaceutically acceptablesalt thereof; (C) a disintegrant in an amount of 3 to 10% by weightbased on the total weight of the composition; and (D) a coating agent.

The composition of the present invention, which has the best combinationand optimum ratio of a disintegrant to a coating agent, shows sufficientstrength and high dissolution rates under various pH environments, andthus, it is useful for the preparation of an excellent solid formulationexhibiting improved drug delivery efficiency and storage stability.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the dissolution rates of amlodipine of thecombined tablets comprising losartan and amlodipine of Examples 1 to 3,and Comparative Examples 1 to 9.

FIG. 2 is a graph showing the dissolution rates of losartan potassium ofthe combined tablets comprising losartan and amlodipine of Examples 1 to3 and Comparative Examples 1 to 9.

FIG. 3 is a graph showing the dissolution rates of amlodipine of thecombined tablets comprising losartan and amlodipine of Examples 1, 4 and5, and Comparative Examples 11 to 13.

FIG. 4 is a graph showing the dissolution rates of losartan potassium ofthe combined tablets comprising losartan and amlodipine of Examples 1, 4and 5, and Comparative Examples 11 to 13.

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment of the present invention, there is provideda pharmaceutical composition for the prevention or treatment ofcardiovascular disorders comprising:

(A) losartan or a pharmaceutically acceptable salt thereof;

(B) amlodipine or a pharmaceutically acceptable salt thereof;

(C) a disintegrant in an amount of 3 to 10% by weight based on the totalweight of the composition; and

(D) a coating agent.

As used herein, the term “cardiovascular disorder” refers to a disordercaused by increased blood pressure or decreased blood flow to heartmuscles due to narrowing or obstruction of a coronary artery thatsupplies blood to the heart. Specifically, the cardiovascular disorderto be prevented or treated by a composition of the present invention maybe selected from the group consisting of angina pectoris, hypertension,arterial vasospasm, cardiac arrhythmia, cardiac hypertrophy, cerebralinfarct, congestive heart failure and myocardial infarction.

As used herein, the term “treatment” refers to (a) inhibition ofdevelopment of a disorder, a disease or a symptom; (b) alleviation of adisorder, a disease or a symptom; or (c) elimination of a disorder, adisease or a symptom. Losartan and amlodipine, pharmacologicalingredients employed in the composition of the present invention,inhibit, eliminate or alleviate the development of a cardiovasculardisorder or its symptom by blocking angiotensin II receptors and calciumchannels, respectively. Therefore, the composition of the presentinvention itself can be a therapeutic composition for a cardiovasculardisorder, and it can also be a therapeutic adjuvant to beco-administered with other pharmacological ingredients to improve thecardiovascular function or blood flow. Thus, as used herein, the term“treatment” or “therapeutics” is intended to include the meaning of“treatment adjuvant” or “therapeutics adjuvant.”

As used herein, the term “prevention” refers to inhibition of occurrenceof a disorder or a disease in a subject who has not been diagnosed tohave a disorder or a disease but has a possibility of developing suchdisorder or disease.

According to a specific embodiment of the present invention, losartan ora pharmaceutically acceptable salt thereof is employed in an amount of15 to 30% by weight based on the total weight of the composition. Morespecifically, it is employed in an amount of 17 to 25% by weight, andmost specifically 18 to 22% by weight.

Losartan used in the present invention may be one of the various formsof pharmaceutically acceptable salts. A useful example of thepharmaceutically acceptable salts is an acid addition salt formed by apharmaceutically acceptable free acid. The free acid may be an organicor inorganic acid.

Examples of pharmaceutically acceptable salts of losartan may includelosartan sodium, losartan potassium, losartan strontium, losartancalcium, losartan magnesium, losartan ammonium or a mixture thereof, butare not limited thereto, and any form of salts conventionally used forthe preparation of a pharmaceutical composition in the art can beemployed. Most specifically, a pharmaceutically acceptable salt oflosartan used in the present invention may be losartan potassium.

Based on a unit dosage form (solid administration form), losartan or apharmaceutically acceptable salt thereof is conventionally employed inan amount of, for example, 10 to 500 mg, specifically 25 to 250 mg, morespecifically 50 to 200 mg, and most specifically 50 to 100 mg.

According to a specific embodiment of the present invention, amlodipineor a pharmaceutically acceptable salt thereof is employed in amount of 3to 20% by weight based on the weight of the losartan or apharmaceutically acceptable salt thereof. More specifically, it isemployed in an amount of 5 to 15% by weight, even more specifically 6 to12% by weight, and most specifically 7 to 9% by weight.

Amlodipine used in the present invention may be one of the various formsof pharmaceutically acceptable salts. Examples of the pharmaceuticallyacceptable salts of amlodipine may include chloride, hydrobromide,sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate,citrate, gluconate, besylate and camsylate salt, but are not limitedthereto, and any form of salts formed by various inorganic or organicacids conventionally used in the art can be employed. Specifically, thepharmaceutically acceptable salt of amlodipine may be amlodipinebesylate or amlodipine camsylate, and more specifically, amlodipinecamsylate. Also, amlodipine,3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate, used in the present invention covers all of itsstereoisomers.

Based on a unit dosage form (solid administration form), amlodipine isconventionally employed in an amount of, for example, 1.25 to 20 mg,specifically 1.875 to 15 mg, more specifically 2.5 to 10 mg, and mostspecifically 5 to 10 mg. The amount of amlodipine described above refersto the amount of free amlodipine present in its solid dosage form.

As used herein, the term “disintegrant” refers to a material thataccelerates disintegration of a solid formulation, especially a tablet,by improving its solubility, enabling an active ingredient of theformulation to be dissolved in a therapeutically effective amount. Theterm “therapeutically effective amount” refers to a sufficient amount ofa pharmacological ingredient to provide therapeutic or preventive effectto a subject, which is thus intended to encompass the meaning of“preventively effective amount.”

A dissolution delay arising from a disintegration delay may be improvedby increasing the amount of a disintegrant, but excessive use of adisintegrant may result in a solid formulation (e.g., a tablet) whichfails to show enough strength to maintain its form/property during thepreparation, packaging, transportation or storage process. Adisintegrant of the present invention may be employed in an amount of2.5 to 30% by weight based on the total weight of the composition,specifically 3 to 10% by weight, and more specifically 5 to 9% byweight.

According to a specific embodiment of the present invention, adisintegrant employed in the present invention may be at least oneselected from the group consisting of sodium starch glycolate,croscarmellose sodium and crospovidone.

As used herein, the term “coating agent” refers to a material thatlowers water permeability and improves mechanical strength and storagestability by modifying the surface of a solid formulation to form anouter shell. By employing a disintegrant at a specific ratio in a solidformulation containing amlodipine and losartan as pharmacologicalingredients, the dissolution rate of the formulation may be improved butits stability may be worsened upon exposure to moisture. Thus, a coatingagent can be additionally employed to increase the strength andstability of the formulation.

As used herein, the term “coating” refers to binding to the surface of amaterial to be coated (modified) without changing the basic physicalproperty of the material. For example, the expression “the surface of asolid formulation is coated with a coating agent” means that moleculesof the coating agent have directly or indirectly bound to a delocalizedarea of the surface of the solid formulation. Therefore, it would beapparent that “coating,” as used herein, is not limited to the caseswhere a layer, which completely covers the surface of a material to becoated is formed. More specifically, the term “coating,” as used herein,refers to binding to the surface of a material, occupying enough surfacearea to obtain desired strength and stability.

According to a specific embodiment of the present invention, the coatingagent is employed in an amount of 1 to 10% by weight based on the totalweight of the composition, more specifically 1 to 5% by weight, and mostspecifically 2 to 4% by weight.

According to a specific embodiment of the invention, the coating agentemployed in the present invention is at least one polymer selected fromthe group consisting of a coating agent containing polyvinyl alcohol(for example, Opadry), hypromellose, and hydroxypropyl cellulose.

According to a specific embodiment of the invention, the hypromellosehas a viscosity of 10 to 30 mPa·s, more specifically 10 to 20 mPa·s, andeven more specifically 10 to 15 mPa·s. According to the presentinvention, it was observed that storage stability decreased uponexposure to moisture if the viscosity of the coating agent was less than10 mPa·s.

According to a specific embodiment of the present invention, the weightratio of the disintegrant to the coating agent in the composition rangesfrom 1.5:1 to 4.0:1. According to the present invention, with regard toa solid formulation which employs amlodipine and losartan aspharmacological ingredients, the dissolution of the pharmacologicalingredients can be improved by employing a disintegrant, and also,declining of strength, stability, and preservability of the formulationcan be prevented by employing a coating agent. Therefore, the ratiobetween these two ingredients which play complementary roles to eachother is important to achieve efficient drug delivery and drugstability. More specifically, the weight ratio of the disintegrant tothe coating agent in the composition of the present invention may be inthe range of 1.9:1 to 3.0:1, even more specifically 2.2:1 to 3.0:1, andmost specifically 2.2:1 to 2.5:1.

According to a specific embodiment of the present invention, thecomposition of the present invention can be formulated into a coatedtablet which shows a thickness increase of 3% or less upon exposure toaccelerated conditions of 40° C. and 75% relative humidity for 5 hours.

According to a specific embodiment of the present invention, thecomposition of the present invention can be formulated into a coatedtablet which shows a mass increase of 5% or less upon exposure toaccelerated conditions of 40° C. and 75% relative humidity for 5 hours.

According to the present invention, a solid formulation prepared byusing a composition of the present invention shows a thickness increaseand a mass increase of 3% or less and 5% or less, respectively, uponexposure to a high humidity environment of 75% relative humidity sincewater absorption is blocked, thereby achieving excellent storagestability.

As such, owing to the best combination and optimum ratio of thedisintegrant to the coating agent, a solid formulation prepared by usingthe composition of the present invention shows excellent dissolutionrate and storage stability.

The composition of the present invention may be formulated into variousforms of solid formulations such as, for example, a tablet, a capsule ormulti-particles, and may be administered by various routes such as, forexample, oral, peroral or hypoglossal route. Specifically, a compositionof the present invention may be formulated into a tablet and orallyadministered. Ingredients of the composition of the present inventionother than the coating agent may be simply mixed and tableted to obtaina plain tablet, which may be coated with the coating agent to obtain afinal tablet. A tablet requires an appropriate hardness, and averagehardness in the rage of 5 kp to 30 kp is preferable. Measurement of theaverage hardness is carried out before applying a coating layer onto thetablet.

Hereinafter, the present invention is explained in detail by Examples.The following Examples are intended to further illustrate the presentinvention without limiting its scope.

EXAMPLES Examples 1 to 3 and Comparative Examples 1 to 9 Preparation ofCombined Tablets I Example 1

-Wet granule part- amlodipine camsylate 7.84 mg (amlodipine 5 mg)butylated hydroxytoluene (BHT) 0.1 mg mannitol 27 mg microcrystallinecellulose 61 mg sodium starch glycolate 17 mg polyvinylpyrrolidone 3.2mg -Roller compacting part- losartan potassium 100 mg microcrystallinecellulose 260 mg crospovidone 18 mg -Final mixing part- magnesiumstearate 3.2 mg -Coating agent- talc 0.25 mg titanium oxide 2.25 mghydroxypropyl cellulose 2.5 mg hypromellose (15 mPa · s) 10 mg ethanol325 mg purified water 85 mg *Ethanol and purified water are evaporatedduring a coating process.

According to the compositions as above, amlodipine camsylate, butylatedhydroxytoluene, mannitol, microcrystalline cellulose, and sodium starchglycolate were put into a high speed mixer; allowed to unite for 7minutes while supplying polyvinylpyrrolidone dissolved in an appropriateamount of water to the high speed mixer as a binder solution; and driedfor 30 minutes using a fluid bed dryer. The dried materials thusobtained were sized using Fitz Mill to prepare wet granules. Also, drygranules were prepared by mixing losartan potassium, microcrystallinecellulose and crospovidone, which were then subjected to compactingprocess using a roller compactor.

The wet and dry granules were mixed, and then lubricated by mixing withmagnesium stearate, a final mixing part. The resulting mixture wastableted with a compression force of about 20 kN using a rotary tabletpress (Sejong Pharmatech, MRC-45) to prepare a losartan 100mg-amlodipine 5 mg combined tablet. After preparing a coating solutionaccording to the specified coating compositions the combined tablet wasfilm-coated with an inflowing air temperature of 50° C. and outflowingair temperature of 40° C. using an automatic coating device (SejongPharmatech, SFC-30), and the resulting tablet was dried at 35° C. for 30minutes to prepare a film-coated tablet.

Example 2

-Wet granule part, roller compacting part and final mixing part- same asExample 1 -Coating agent- Opadry 85f18422 15 mg (polyvinyl alcohol 40%,titanium oxide 25%, polyethylene glycol 20.2%, and talc 14.8%) purifiedwater 100 mg *Purified water is evaporated during a coating process.

A combined tablet was prepared by repeating the procedure of Example 1.

Example 3

-Wet granule part, roller compacting part and final mixing part- same asExample 1 -Coating agent- Opadry 80W AMB 15 mg (polyvinyl alcohol40~50%, titanium oxide 20~30%, talc about 20%, lecithin about 2%,Xanthan Gum about 1%) purified water 100 mg *Purified water isevaporated during a coating process.

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 1

-Wet granule part- amlodipine camsylate 7.84 mg (amlodipine 5 mg)butylated hydroxytoluene 0.1 mg mannitol 27 mg microcrystallinecellulose 61 mg sodium starch glycolate 6 mg polyvinylpyrrolidone 3.2 mg-Roller compacting part- losartan potassium 100 mg microcrystallinecellulose 260 mg crospovidone 6 mg -Final mixing part- magnesiumstearate 3.2 mg -Coating agent- same as Example 1

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 2

Wet granule part, roller compacting part and final mixing part—

-   -   same as Comparative Example 1

Coating agent—

-   -   same as Example 2

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 3

Wet granule part, roller compacting part and final mixing part—

-   -   same as Comparative Example 1

Coating agent—

-   -   same as Example 3

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 4

-Wet granule part- amlodipine camsylate 7.84 mg (amlodipine 5 mg)butylated hydroxytoluene 0.1 mg mannitol 27 mg microcrystallinecellulose 61 mg sodium starch glycolate 30 mg polyvinylpyrrolidone 3.2mg -Roller Compacting part- losartan potassium 100 mg microcrystallinecellulose 260 mg crospovidone 30 mg -Final mixing part- magnesiumstearate 3.2 mg -Coating agent- same as Example 1

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 5

Wet granule part, roller compacting part and final mixing part—

-   -   same as Comparative Example 4

Coating agent—

-   -   same as Example 2

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 6

Wet granule part, roller compacting part and final mixing part—

-   -   same as Comparative Example 4

Coating agent—

-   -   same as Example 3

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 7

-Wet granule part, roller compacting part and final mixing part- same asExample 1 -Coating agent- talc 0.25 mg titanium oxide 2.25 mghydroxypropyl cellulose 2.5 mg hypromellose (3 mPa · s) 10 mg ethanol325 mg purified water 85 mg *Ethanol and purified water are evaporatedduring a coating process.

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 8

-Wet granule part, roller compacting part and final mixing part- same asExample 1 -Coating agent- talc 0.25 mg titanium oxide 2.25 mghydroxypropyl cellulose 2.5 mg hypromellose (4.5 mPa · s) 10 mg ethanol325 mg purified water 85 mg * Ethanol and purified water are evaporatedduring a coating process.

A combined tablet was prepared by repeating the procedure of Example 1.

Comparative Example 9

-Wet granule part, roller compacting part and final mixing part- same asExample 1 -Coating agent- talc 0.25 mg titanium oxide 2.25 mghydroxypropyl cellulose 2.5 mg hypromellose (6 mPa · s) 10 mg ethanol325 mg purified water 85 mg *Ethanol and purified water are evaporatedduring a coating process.

A combined tablet was prepared by repeating the procedure of Example 1.

The compositions of combined formulations prepared in Examples 1 to 3and Comparative Examples 1 to 9 are shown in Table 1 below.

TABLE 1 Comp. Comp. Comp. Comp. Comp. Comp. Comp. Comp. Comp.Composition Ex. 1 Ex. 2 Ex. 3 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7Ex. 8 Ex. 9 Disintegrant ratio 6.8 6.8 6.8 2.5 2.5 2.5 11.2 11.2 11.26.8 6.8 6.8 (%) Wet Amlodipine 7.84 7.84 7.84 7.84 7.84 7.84 7.84 7.847.84 7.84 7.84 7.84 granule camsylate BHT 0.1 0.1 0.1 0.1 0.1 0.1 0.10.1 0.1 0.1 0.1 0.1 Mannitol 27 27 27 27 27 27 27 27 27 27 27 27Microcrystalline 61 61 61 61 61 61 61 61 61 61 61 61 cellulose Sodiumstarch 17 17 17 6 6 6 30 30 30 17 17 17 glycolate Poly- 3.2 3.2 3.2 3.23.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 vinylpyrrolidone Roller Losartan 100 100100 100 100 100 100 100 100 100 100 100 compacting potassiumMicrocrystalline 260 260 260 260 260 260 260 260 260 260 260 260cellulose Crospovidone 18 18 18 6 6 6 30 30 30 18 18 18 Final Magnesium3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Mixing stearate CoatingTalc 0.25 — — 0.25 — — 0.25 — — 0.25 0.25 0.25 agent Titanium oxide 2.25— — 2.25 — — 2.25 — — 2.25 2.25 2.25 Hydroxypropyl 2.5 — — 2.5 — — 2.5 —— 2.5 2.5 2.5 cellulose Hypromellose 10 — — 10 — — 10 — — — — — (15 mPa· s) Hypromellose — — — — — — — — — 10 — — (3 mPa · s) Hypromellose — —— — — — — — — — 10 — (4.5 mPa · s) Hypromellose — — — — — — — — — — — 10(6 mPa · s) Opadry 85F18422 — 15 — — 15 — — 15 — — — — Opadry 80W AMB —— 15 — — 15 — — 15 — — — Total weight 512.3 512.3 512.3 489.3 489.3489.3 537.3 537.3 537.3 512.3 512.3 512.3 (mg/tablet)

Test Example 1 Amlodipine Dissolution Test

Combined tablets of losartan potassium and amlodipine obtained inExamples 1 to 3 and Comparative Examples 1 to 9 were subjected to anamlodipine dissolution test under the following conditions. The resultsare shown in FIG. 1.

Dissolution conditions—

-   -   Eluent: artificial gastric juice (pH 1.2) 900 mL    -   Method (apparatus): USP paddle method, 50 rpm    -   Temperature: 37° C.

Analysis conditions—

-   -   Column: stainless steel column (inner diameter: 4.6 mm, length:        15 cm) packed with octadecylsilyl-silica gel for liquid        chromatography (diameter of 5 μm)    -   Mobile phase: methanol:0.03M potassium dihydrogen phosphate        solution (600:400, v/v)    -   Detector: ultraviolet spectrophotometer (wavelength 350 nm)    -   Flow rate: 1.5 mL/min.    -   Injection volume: 20 μL

As a result, Examples 1, 2 and 3 and Comparative Examples 4 to 9, inwhich the disintegrant ratio, or the ratio of a disintegrant to acomposition, was 6.0% or higher, showed excellent dissolution rates ofamlodipine, whereas Comparative Examples 1, 2 and 3, in which thedisintegrant ratio was less than 3.0%, showed low dissolution rates (seeFIG. 1).

Test Example 2 Losartan Potassium Dissolution Test

Combined tablets of losartan potassium and amlodipine obtained inExamples 1 to 3 and Comparative Examples 1 to 9 were subjected to alosartan potassium dissolution test under the following conditions. Theresults are shown in FIG. 2.

Dissolution conditions—

-   -   Eluent: artificial gastric juice (pH 1.2), 900 mL    -   Method (apparatus): USP paddle method, 50 rpm    -   Temperature: 37° C.

Analysis conditions—

-   -   Column: stainless steel column (inner diameter: 4.6 mm, length:        15 cm) packed with octadecylsilyl-silica gel for liquid        chromatography (diameter of 5 μm)    -   Mobile phase:    -   mobile phase A—phosphate buffer: acetonitrile (850:150, v/v)    -   mobile phase B—acetonitrile

TABLE 2 Gradient system Time (min) Mobile Phase A % Mobile Phase B % 080 20 10 40 60 11 80 20 15 80 20

-   -   Detector: ultraviolet spectrophotometer (wavelength 250 nm)    -   Flow rate: 1.5 mL/min    -   Injection volume: 10 μL

As a result, Examples 1, 2 and 3 and Comparative Examples 4 to 9, inwhich the ratio of a disintegrant was 6.0% or higher, showed excellentdissolution rates of losartan potassium, whereas Comparative Examples 1,2 and 3, in which the disintegrant ratio was less than 3.0%, showed lowdissolution rates (see FIG. 2).

Test Example 3 Moisture Exposure Test

Combined tablets of losartan potassium and amlodipine obtained inExamples 1 to 3 and Comparative Examples 4 to 9 were subjected to amoisture exposure test under the following conditions. The results areshown in Table 3 below.

TABLE 3 Results of a moisture exposure test for the coated tablets ofExamples 1 to 3 and Comparative Examples 4 to 9. Comp. Comp. Comp. Comp.Comp. Comp. Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 40° C.75% Mass increase 2.7 1.4 0.8 6.9 6.5 4.8 6.0 4.9 4.3 5 h (%) exposureThickness 1.6 0.9 0.5 4.1 3.7 3.5 3.5 3.0 2.7 increase (%) 50° C. 75%Mass increase 3.8 2.7 2.0 7.2 7.0 6.9 6.7 5.7 5.2 5 h (%) exposureThickness 2.5 1.9 1.2 4.7 4.2 4.0 4.0 3.4 3.1 increase (%) 40° C. 75%No. of ruptured 0 0 0 7 7 6 6 5 4 24 h tablets out of 10 exposuretablets 50° C. 75% No. of ruptured 0 0 0 9 8 8 8 8 6 24 h tablets out of10 exposure tablets

The coated tablets of Examples 1 to 3, which employed at least one typeof to high molecular compound selected from the group consisting ofpolyvinyl alcohol, hypromellose (viscosity: 10 mPa·s or higher), andhydroxypropyl cellulose as a coating agent, showed excellent storagestability. In contrast, the coated tablets of Comparative Examples 7 to9, which employed two types of high molecular compound as a coatingagent, hypromellose (viscosity: 10 mPa·s or less) and hydroxypropylcellulose, showed poor storage stability upon exposure to moisture ascompared to Examples 1 to 3. Meanwhile, the coated tablets ofComparative Examples 4 to 6, as compared to Examples 1 to 3, had thesame compositions of coating agents, but the disintegrant ratio was11.2% which is higher by about 65%, and thus the thickness increase,mass increase and the number of damaged tablets were much higher uponexposure to moisture.

Test Example 4 Accelerated Stability Test

Based on the results of Test Examples 1 to 3, the combined tablets oflosartan potassium and amlodipine prepared in Examples 1 to 3, whichshowed good dissolution rates and storage stability upon exposure tomoisture, were subjected to a stability test under acceleratedconditions described below. The results are shown in Table 4 below.

<Accelerated Storage Chamber Conditions>

(1) Temperature: 50° C.±2° C.

(2) Package: HDPE bottle packaging

Test timings—Initial and after 28 days of storage

Analysis conditions

-   -   Amlodipine related substance: same as the analysis conditions of        Test Example 1.    -   Losartan related substance: same as the analysis conditions of        Test Example 2.

TABLE 4 50° C., HDPE bottle packaging, Initial 28 days of storageAmlodipine Losartan Amlodipine Losartan Sam- related related relatedrelated ple substances (%) substances (%) substances (%) substances (%)Ex. 1 0.02 0.01 0.04 0.03 Ex. 2 0.01 0.02 0.11 0.09 Ex. 3 0.03 0.01 0.120.13

As shown in Table 4, the amounts of related substance production werewithin allowable ranges in Examples 1 to 3. But the tablets of Examples2 and 3, in which polyvinyl alcohol was employed, showed higherincreases in the production of related substances as compared to thecoated tablets of Example 1, in which hypromellose was employed as acoating agent.

The results of Test Examples 1 to 4 indicated that that among thecompositions of a coating agent specified for Examples 1 to 3 andComparative Examples 1 to 9, such as hypromellose with variousviscosities and Opadry 58F18422 and 80W AMB which contain polyvinylalcohol, most preferable was hypromellose with a viscosity of 15 mPa·s,which allowed Example 1 to show the best storage stability upon exposureto moisture and best stability under accelerated conditions.

Examples 4 and 5, and Comparative Examples 10 to 13 Preparation ofCombined Formulations II

Combined formulations were prepared according to the compositions of thewet granule part, roller compacting part and final mixing part whichwere the same as Example 1. Also, they were prepared according to thecompositions of the coating agent as shown in Table 5 below, in whichthe same constituents were employed as Example 1, but the amount of eachconstituent was either increased or decreased by a specific ratiorelative to Example 1.

TABLE 5 Composition of combined formulations of Examples 4 and 5, andComparative Examples 10 to 13 Comp. Comp. Comp. Comp. Composition Ex. 10Ex. 11 Ex. 12 Ex. 4 Ex. 5 Ex. 13 Coating Talc — 0.1 0.15 0.2 0.3 0.4agent Titanium oxide — 0.9 1.35 1.8 2.7 3.6 Hydroxypropyl cellulose —1.0 1.5 2.0 3.0 4.0 Hypromellose (15 mPa · s) — 4.0 6.0 8.0 12.0 16.0Coating agent 0 6.0 9.0 12.0 18.0 24.0 Total weight (mg/tablet) 497.3503.3 506.3 509.3 515.3 521.3

TABLE 6 The disintegrant to coating agent ratios in combinedformulations of Examples 1, 4 and 5, and Comparative Examples 10 to 13.Comp. Comp. Comp. Ex. 10 Ex. 11 Ex. 12 Ex. 4 Ex. 1 Ex. 5 Comp. Ex. 13Mass of 35 35 35 35 35 35 35 disintegrant (mg) Mass of 0 6 9 12 15 18 24coating agent (mg) Disintegrant:coating — 5.8:1 3.9:1 2.9:1 2.3:1 1.9:11.5:1 agent ratio

Test Example 5 Moisture Exposure Test

The tablets of Examples 1, 4 and 5, and Comparative Examples 10 to 13were subjected to a moisture exposure test by repeating the procedure ofTest Example 4. The results are shown in table 7.

TABLE 7 Results of moisture exposure test for combined formulations ofExamples 1, 4 and 5, and Comparative Examples 10 to 13. Comp. Comp.Comp. Comp. Ex. 10 Ex. 11 Ex. 12 Ex. 4 Ex. 1 Ex. 5 Ex. 13 40° C. 75%Mass increase (%) 5.2 4.6 4.3 3.0 2.7 2.2 1.5 5 h exposure Thicknessincrease 3.6 2.9 2.7 1.9 1.6 1.3 1.1 (%) 50° C. 75% Mass increase (%)6.8 5.3 5.1 4.1 3.8 2.5 1.7 5 h exposure Thickness increase 4.1 3.3 3.22.7 2.5 1.5 1.3 (%) 40° C. 75% Number of ruptured — 4 3 0 0 0 0 24 htablets out of 10 exposure tablets 50° C. 75% Number of ruptured — 6 5 00 0 0 24 h tablets out of 10 exposure tablets

The coated tablets of Examples 1, 4 and 5, and Comparative Example 13,in which the disintegrant to coating agent ratio was 3.0:1 or lower,showed good storage stability, but the plain tablets of ComparativeExample 10 and the coated tablets of Comparative Examples 11 and 12, inwhich the disintegrant to coating agent ratio was 3.9:1 or higher,showed a mass increase and a thickness increase of 5.0% or more and 3.0%or more, respectively. Especially, as for the tablets having thedisintegrant to coating tablet disintegrant of 3.9:1 or higher as in thecase with coated tablets of Comparative Examples 11 and 12, the higherthe ratio, the more tablets became swollen and ruptured, exhibitingtheir poor storage stability.

Test Example 6 Amlodipine Dissolution Test

Tablets of Examples 1, 4 and 5 and Comparative Examples 11 to 13 weresubjected to a dissolution test by repeating the procedure of TestExample 1. As a result, Examples 1, 4 and 5 and Comparative Examples 11and 12, in which the disintegrant to coating agent ratio was 1.9:1 orhigher, showed high dissolution rates, whereas Comparative Example 13,in which the disintegrant to coating agent ratio was 1.5:1, showed lowdissolution rate (see FIG. 3).

Test Example 7 Losartan Potassium Dissolution Test

Tablets of Examples 1, 4 and 5 and Comparative Examples 11 to 13 weresubjected to a dissolution test by repeating the procedure of TestExample 2. As a result, Examples 1, 4 and 5 and Comparative Examples 11and 12, in which the disintegrant to coating agent ratio was 1.9:1 orhigher, showed high dissolution rates, whereas Comparative Example 13,in which the disintegrant to coating agent ratio was 1.5:1, showed lowdissolution rate (see FIG. 4).

The results of Test Examples 5 to 7 indicated that the coated tablets ofExamples 1, 4 and 5, in which the disintegrant to coating agent ratioranged from about 1.9:1 to about 2.9:1, showed the best storagestability upon moisture exposure and best dissolution rates ofamlodipine and losartan potassium.

1-15. (canceled)
 16. A pharmaceutical composition comprising: (A)losartan or a pharmaceutically acceptable salt thereof; (B) amlodipineor a pharmaceutically acceptable salt thereof; (C) a disintegrant in anamount of 3 to 10% by weight based on the total weight of thecomposition; and (D) a coating agent.
 17. The composition of claim 16,wherein the losartan or the pharmaceutically acceptable salt thereof iscontained in an amount of 15 to 30% by weight based on the total weightof the composition.
 18. The composition of claim 16, wherein theamlodipine or the pharmaceutically acceptable salt thereof is containedin an amount of 3 to 20% by weight based on the weight of the losartanor the pharmaceutically acceptable salt thereof.
 19. The composition ofclaim 16, wherein the amlodipine or the pharmaceutically acceptable saltthereof is contained in an amount of 5 to 15% by weight based on theweight of the losartan or the pharmaceutically acceptable salt thereof.20. The composition of claim 17, wherein the amlodipine or thepharmaceutically acceptable salt thereof is contained in an amount of 5to 15% by weight based on the weight of the losartan or thepharmaceutically acceptable salt thereof.
 21. The composition of claim16, wherein the disintegrant is contained in an amount of 5 to 9% byweight based on the total weight of the composition.
 22. The compositionof claim 16, wherein the disintegrant is at least one selected from thegroup consisting of sodium starch glycolate, croscarmellose sodium andcrospovidone.
 23. The composition of claim 21, wherein the disintegrantis at least one selected from the group consisting of sodium starchglycolate, croscarmellose sodium and crospovidone.
 24. The compositionof claim 16, wherein the coating agent is contained in an amount of 1 to10% by weight based on the total weight of the composition.
 25. Thecomposition of claim 16, wherein the coating agent is contained in anamount of 2 to 4% by weight based on the total weight of thecomposition.
 26. The composition of claim 16, wherein the coating agentis at least one selected from the group consisting of a coating agentcontaining polyvinyl alcohol, hypromellose, and hydroxypropyl cellulose.27. The composition of claim 24, wherein the coating agent is at leastone selected from the group consisting of a coating agent containingpolyvinyl alcohol, hypromellose, and hydroxypropyl cellulose.
 28. Thecomposition of claim 25, wherein the coating agent is at least oneselected from the group consisting of a coating agent containingpolyvinyl alcohol, hypromellose, and hydroxypropyl cellulose.
 29. Thecomposition of claim 26, wherein the hypromellose has a viscosity of 10to 30 mPa·s.
 30. The composition of claim 16, wherein the weight ratioof the disintegrant to the coating agent in the composition ranges from1.5:1 to 4.0:1.
 31. The composition of claim 16, wherein the weightratio of the disintegrant to the coating agent in the composition rangesfrom 1.9:1 to 3.0:1.
 32. The composition of claim 21, wherein the weightratio of the disintegrant to the coating agent in the composition rangesfrom 1.9:1 to 3.0:1.
 33. The composition of claim 16, wherein thecomposition can be formulated into a coated tablet which shows athickness increase of 3% or less upon exposure for 5 hours toaccelerated conditions of 40° C. and 75% relative humidity.
 34. Thecomposition of claim 16, wherein the composition can be formulated intoa coated tablet which shows a mass increase of 5% or less upon exposurefor 5 hours to accelerated conditions of 40° C. and 75% relativehumidity.
 35. The method for the prevention or treatment of acardiovascular disorder comprising administration of the composition ofclaim 16, wherein the cardiovascular disorder is selected from the groupconsisting of angina pectoris, hypertension, arterial vasospasm, cardiacarrhythmia, cardiac hypertrophy, cerebral infarct, congestive heartfailure and myocardial infarction.